The noble gases were previously known as inert gases because of their perceived lack of participation in any chemical reactions. The reason for this is that their outmost electron shells (valence shells) are completely filled, so that they have little tendency to acquire or lose electrons. It is now known that most of these gases in fact do react to form chemical compounds, such as xenon tetrafluoride. Hence, they have been renamed to noble gases. However, a large amount of energy is required to drive such reactions, usually in the form of heat, pressure, or radiation, often assisted by catalysts. The resulting compounds often need to be kept in moisture-free conditions at low temperatures to prevent rapid decomposition back into their elements.

The term inert may also be applied in a relative sense. For example, molecular nitrogen is inert under ordinary conditions, existing as diatomic molecules, N
2. The presence of a strong triple covalent bond in the N
2 molecule renders it unreactive under normal circumstances. Nevertheless, nitrogen gas does react with the alkali metal lithium to form compound lithium nitride (Li3N), even under ordinary conditions. Under high pressures and temperatures and with the right catalysts, nitrogen becomes more reactive; the Haber process uses such conditions to produce ammonia from atmospheric nitrogen.

Inert atmospheres consisting of gases such as argon, nitrogen, or helium are commonly used in chemical reaction chambers and in storage containers for oxygen-sensitive or water-sensitive substances, to prevent unwanted reactions of these substances with oxygen or water.

The Federal Insecticide, Fungicide, and Rodenticide Act divides the ingredients in pesticides into two groups: active and inert. An inert chemical, under this context, is one that does not have a toxic effect on the species the pesticide is meant to combat, but that does not rule out that it may still have a biological activity on other species, including being toxic to humans. Solvents, propellents, preservatives, among others, are thus considered "inert ingredients"[1] in pesticides.[2]

In the field of weapons and explosives, an inert munition is one in which all energetic material such as primers, fuses, and the explosive or incendiary materials within them have been removed or otherwise rendered harmless. Inert munitions are used in military and naval training, and they are also collected and displayed by public museums, or by private parties. See also military dummy. Typically, American and NATO inert munitions are painted entirely in light blue and/or have the word "INERT" stenciled on them in prominent locations.